1. Field of the Invention
This invention relates to certain tricyclic substituted diazabicyclo[3.2.1] octane derivatives which selectively bind to certain monoamine receptor subtypes. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinsonism. Furthermore compounds of this invention may be useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. These tricyclic substituted diazabicyclo[3.2.1] octane derivatives of the invention interact with certain noradrenalin, dopamine and serotonin receptor subtypes. The demonstration of atypical antipsychotic profiles (clozapine-like) in key animal behavioral models is also described for certain compounds of this invention.
2. Description of the Related Art
Schizophrenia and psychosis are terms used to describe a group of illnesses of unknown origin which affect approximately 2.5 million people in the United States. These disorders of the brain are characterised by a variety of symptoms which are classified as positive symptoms (disordered thought, hallucinations and delusions) and negative symptoms (social withdrawal and unresponsiveness). These disorders have an age of onset in adolescence or early adulthood and persist for many years. The disorders tend to become more severe during the patients lifetime and can result in prolonged institutionalization. In the US today, approximately 40% of all hospitalized psychiatric patients suffer from schizophrenia.
During the 1950's physicians demonstrated that they could successfully treat psychotic patients with medications called neuroleptics; this classification of antipsychotic medication was based largely on the activating (neuroleptic) properties of the nervous system by these drugs. Subsequently, neuroleptic agents were shown to increase the concentrations of dopamine metabolites in the brain suggesting altered neuronal firing of the dopamine system. Additional evidence indicated that dopamine could increase the activity of adenylate cyclase in the corpus striatum, an effect reversed by neuroleplic agents. Thus, cummulative evidence from these and later experiments strongly suggested that the neurotransmitter dopamine was involved in schizophrenia.
One of the major actions of antipsychotic medication is the blockade of dopamine receptors in brain. Several dopamine systems appear to exist in the brain and at least three classes of dopamine receptors appear to mediate the actions of this transmitter. These dopamine receptors differ in their pharmacological specificity. They were originally classified based upon the known pharmacology of different chemical series. The class of compounds known as butyrophenones, which includes many potent antipsychotic drugs, are weakly active at the adenylate cyclase-activating dopamine receptor, now known as a D1 dopamine receptor. In contrast, they labelled other dopamine receptors (called D2 receptors) in the subnanomolar range and a third type D3 in the nanomolar range. Phenothiazines possess nanomolar affinity for all three types of dopamine receptors. Other drugs have been developed with great specificity for the D1 subtype receptor.
Recently, a new group of drugs (such as sulpiride and clozapine) have been developed with a lesser incidence of extrapyramidal side effects than classical neuroleptics. In addition, there is some indication that they may be more beneficial in treating negative symptoms in some patients. Since all D2 blockers do not possess a similar profile, hypotheses underlying the differences have been investigated. The major differences have been in the anticholinergic actions of the neuroleptics as well as the possilility that the dopamirie receptors may differ in motor areas from those in the limbic areas thought to mediate the antipsychotic responses. The existence of the D3 and other as yet undiscovered dopamine receptors may contribute to this profile. Some of the atypical compounds possess similar activity at both D2 and D3 receptors. The compounds of the present invention fall into this general class of molecules.
Using molecular biological techniques it has been possible to clone cDNAs coding for each of the pharmacologically defined receptors. There are at least two forms of D1, and two forms of D2 dopamine receptors. In addition. there is .it least one form of D3 dopamine receptor.
The tricyclic substituted diazabicyclo[3.2.1] octane derivatives of the invention possess differential affinities for each receptor subtype as well as for certain other noradrenergic and seretonergic receptor subtypes.
French patent application 71.27825 discloses compounds of the general formula: ##STR3## and their salts, in which: X signifies either an atom of sulfur, or an atom of oxygen, or an atom of selenium;
Y signifies either a --CH.dbd.CH-- group, or an atom of sulfur PA1 Z signifies either a single bond, or a group --CH.sub.2 --, or an atom of oxygen, or NR4; PA1 A signifies either hydrogen or, while being bonded together, yet another bond; PA1 R.sub.1 signifies either hydrogen, or an atom of halogen, or trifluoromethyl, or an amino group, or an alkyl group, or an alkoxy group; PA1 R.sub.2 and R.sub.3 signify either an atom of hydrogen or, while being bonded together, a bivalent part --CH2CH2--; PA1 R.sub.4 signifies either an alkyl group, a hydroxyalkyl having from 1-4 carbon atoms, cycloalkyl, cycloalkylalkyl having 3-6 carbon atoms, phenyl or benzyl. PA1 Z is hydrogen, amino or NHR.sub.6 where R.sub.6 is straight or branched chain lower alkyl having 1-6 carbon atoms; PA1 T is hydrogen, halogen, hydroxy, or lower alkoxy having 1-6 carbon atoms; and PA1 A is methylene, carbonyl or CHOH.